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2642 VISTA Targeting Modulates Tumor-Infiltrating Myeloid Cells to Overcome Adaptive Resistance

Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster III
Hematology Disease Topics & Pathways:
immune cells, Cell Lineage
Monday, December 7, 2020, 7:00 AM-3:30 PM

Janet Lines, PhD1*, Evelien Schaafsma, MA1*, Walburga Croteau1*, Mohamed ElTanbouly2*, Elizabeth Nowak1*, Nicole Smits3*, Cecilia Webber1*, Aurelien Sarde4*, Dina Rabadi1*, Jie Deng5*, Bruce R. Blazar, MD6, Chao Cheng7* and Randolph Noelle1*

1Geisel School of Medicine at Dartmouth, Lebanon, NH
2Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH
31Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, Lebanon
4Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, Lebanon
5Department of Radiation Oncology, UCLA, Los Angeles, CA
6Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN
7Department of Medicine, Baylor College of Medicine, Houston, TX

Over the last decade, the field of cancer immunotherapy has evolved dramatically with the advent of “immune checkpoint therapy” (ICT) in which monoclonal antibody (mAb) targeting of the immune checkpoints CTLA-4 or PD-1 can unleash the immune system’s ability to destroy established tumors in both mice and some cancer patients (Fritz and Lenardo, 2019, Iwai, 2004, Leach, 1996). Despite improved T cell responses, objective responses with ICT are only observed in a minority of treated patients, and are not effective against all tumor types. Therefore, a great demand for cancer immunotherapy is to understand the individual and combined mechanisms of different therapies, to allow informed combination treatment to increase efficacy across a larger proportion of patients.

Single-cell RNA sequencing (scRNAseq) has shown that anti-CTLA-4 more effectively enhances cell cycle and effector memory pathways, while anti-PD-1 mostly enhances metabolism and effector function (Gubin et al., 2014). VISTA is a negative checkpoint regulator prominently expressed in the tumor microenvironment (TME) of a wide variety of cancers. In the CT26 preclinical model of colorectal cancer, monotherapy of small tumors (40 mm3) with a blocking anti-VISTA mAb (clone 13F3) markedly slowed tumor growth. Mice bearing large tumors (600mm3) all died despite anti-PD-1 and anti-CTLA4 mAb treatment, indicating checkpoint resistance. Inclusion of anti-VISTA led to complete rejection of 50% of tumors (Fig. 1). The underlying therapeutic mechanisms of enhanced anti-tumor immunity was investigated by high-dimensional scRNAseq of the CD45+ immune infiltrate 10 days after treatment initiation. In both settings, the mechanism of anti-VISTA impact on myeloid function was defined, with specific induction of myeloid signaling and antigen-presentation pathways. Suppression assays showed that the myeloid infiltrate was less suppressive to T cells. Multi-spectral imaging was used to characterize the distribution of infiltrating immune cells, and cell-cell contacts of immune cells were quantified. Along with unique transcriptional signatures, improved cellular interactions of anti-VISTA treated tumors supported increased antigen presentation.

Transcriptional analysis of tetramer-enriched tumor-specific CD8 T cells showed that anti-VISTA therapy induced T cell pathways highly distinct from the anti-exhaustion effects of anti-PD-1 therapy, contrasting the mechanisms of anti-VISTA with traditional checkpoint blockade.

These data document the unique and complementary impact of targeting VISTA in contrast to PD-1 and CTLA-4 in both the myeloid and T cell lineages. These mechanistic insights strongly support the use of anti-VISTA to overcome the checkpoint resistance seen in contemporary treatments involving PD-1.

Disclosures: Sarde: Amphivena Therapeutics: Current Employment, Current equity holder in private company. Blazar: Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; Tmunity: Other: Co-founder; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding; KidsFirst Fund: Research Funding. Noelle: Immunext: Current equity holder in private company, Patents & Royalties: 10035857, 9631018, 9217035, 8501915, 8465740, 8236304, 8231872, 9890215 and 9381244.

*signifies non-member of ASH